CN102802626B - 作为肌肉刺激剂的烟酸和/或葫芦巴碱 - Google Patents
作为肌肉刺激剂的烟酸和/或葫芦巴碱 Download PDFInfo
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- CN102802626B CN102802626B CN201080025327.4A CN201080025327A CN102802626B CN 102802626 B CN102802626 B CN 102802626B CN 201080025327 A CN201080025327 A CN 201080025327A CN 102802626 B CN102802626 B CN 102802626B
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- trigonelline
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Abstract
本发明涉及烟酸和/或葫芦巴碱化合物在活动期间提高肌肉重量或在不活动期间抑制肌肉损失的用途。
Description
发明领域
本发明涉及烟酸和/或葫芦巴碱化合物用于在活动期间增加肌肉重量或在不活动期间抑制肌肉损失的用途。
发明背景
骨骼肌最具特征性的特征之一是其适应于不同刺激的可观能力。在一生中骨骼肌一直在适应于内部改变(衰老/老年性肌肉萎缩,导致肌肉损失)或外部改变(体力活动导致肌肉肥大;而损伤导致肌肉恢复;卧床休息导致肌肉萎缩)。这些影响改变不同骨骼肌纤维的结构变量、生物化学变量和分子变量。对肌纤维的适应而言,卫星细胞(所谓的骨骼肌干细胞)的活化和生肌分化(myogenicdifferentiation)是必需的。例如,在运动训练后卫星细胞与正在扩大或修复的肌细胞融合在一起。
烟酸(niacin)也称作维生素B3或尼克酸(nicotinicacid),是预防营养缺乏症糙皮病的水溶性维生素。这是具有式(I)定义的分子式C6H5NO2的有机化合物。
其为第3位上具有羧基(COOH)的吡啶衍生物。维生素B3的其它形式包括相应的酰胺,尼克酰胺(“烟酰胺”),其中羧基被氨甲酰基(CONH2)代替,以及更复杂的酰胺和多种酯。术语烟酸、尼克酰胺和维生素B3可互换使用,表示该家族分子的任一个,因为它们具有共同的生物化学活性。
葫芦巴碱(Trigonelline)是具有式(II)定义的化学式C7H7NO2的生物碱。
葫芦巴碱是排泄于尿中的烟酸(维生素B3)代谢产物。其通过对烟酸的氮原子添加甲基而形成。葫芦巴碱还存在于咖啡中,在咖啡中其可通过预防细菌Streptococcusmutans粘附在牙齿上而帮助预防龋齿。
US2005/0226948(Leeetal)公开了含有4-羟基异亮氨酸和大量其他化合物(包括烟酸和葫芦巴碱)的葫芦巴种子提取物。这些组合被用于增加进入肌细胞的葡萄糖运输。
US2007/0105793(Hendrix)公开了用于治疗高脂血症、高胆固醇血症和高甘油酯血症的组合物,其含有烟酸和衍生物。
US2007/0259861(Krantz)公开了下述组合物,所述组合物含有与前列腺素模拟物(其可包括多种烟酸衍生物)组合的非固醇类抗炎药(NSAID)。这些组合被用于缓解炎症和/或疼痛。
发明内容
根据本发明已发现,烟酸、葫芦巴碱或烟酸和葫芦巴碱二者的组合能够在训练期间增加肌肉重量,并且能够在较少活动或不活动期间减少肌肉损失。因此,本发明的一个方面是烟酸和/或葫芦巴碱和/或其盐或酯在制造下述营养药物或食物中的用途,所述营养药物或食物用于在训练期间增加肌肉重量,或在不活动期间减少肌肉损失量。本发明的另一方面是在运动期间增加肌肉量的方法,所述方法包括对进行训练的个体施用有效量的烟酸和/或葫芦巴碱或其盐或酯,并观察肌肉量增加。本发明的又一方面是减少处于肌肉损失风险下的较少活动或不活动的人的肌肉损失的方法,所述方法通过施用烟酸和/或葫芦巴碱或其盐或酯并保留肌肉来实现。在一些优选的实施方案中,烟酸和/或葫芦巴碱或其盐或酯与蛋白质和维生素(尤其包括维生素D和/或其代谢产物,例如25-羟基维生素D3)的最优营养供应一起使用。
附图说明
图1展示了葫芦巴碱对小鼠肌细胞中肌管形成的体外效应。
图2展示了来自于对照和经处理的小鼠(肥大模型)的腓肠肌湿重(相对于体重(BW))。
图3展示了针对对照和经处理的小鼠,尾悬挂模型(tailsuspensionmodel)腓肠肌湿重相对于BW的结果。
图4展示了踏车奔跑(treadmillrunning)后腓肠肌的湿重。
在说明书和权利要求书通篇中使用时,适用以下定义:
在本文中使用时,术语“营养药物”表示在营养和药物两种应用领域中的有用性。因此,根据本发明的“营养药物”能够用作食物、饲料和饮料补剂,膳食补剂以及药物配制物,其可以是固体(例如胶囊或片剂)或液体(例如溶液或悬浮液)。
“烟酸”是指适用于营养药物的任何形式的烟酸,包括烟酸、烟酰胺、其盐或酯,或其水合物。
“烟酸盐或酯”是指可用于将烟酸配制成营养药物可接受形式、或配制成食品的任何盐或酯形式的烟酸。盐或酯应当是适用的监管机构允许被摄食的盐或酯。合适的烟酸盐的例子包括硫酸盐、硫酸氢盐、氯化物、磷酸盐和柠檬酸盐。合适的烟酸酯的例子包括甲基酯氯化物和乙基酯氯化物。
“葫芦巴碱”是指适用于营养药物的任何形式的葫芦巴碱,包括葫芦巴碱,和葫芦巴碱盐或酯的葫芦巴碱水合物。
“葫芦巴碱盐或酯”是指可用于将葫芦巴碱配制成营养药物可接受的形式或配制成食品的任何盐或酯形式的葫芦巴碱。盐或酯应当是适用的监管机构允许被摄食的盐或酯。合适的葫芦巴碱盐的例子包括硫酸盐、硫酸氢盐、氯化物、磷酸盐和柠檬酸盐。合适的葫芦巴碱酯的例子包括甲基酯氯化物和乙基酯氯化物。
“预防”包括降低症状和/或病症的严重性,降低发生症状或病症的风险,增加发生症状或病症之前的时间,早期干预,以及使症状或病症不出现(negationofasymptomorcondition)。
“观察”可由使用葫芦巴碱或烟酸的个体进行或由第三方进行。观察可在一段时间内进行,并可追踪整个施用长度。典型的施用期间可以是一周、一个月、三个月、六个月或其他想要的时间段。
烟酸可存在于酵母、肉、家禽、红鱼(例如金枪鱼、三文鱼)、谷物(尤其是经强化的谷物)、豆类和种子中。奶、绿叶蔬菜、咖啡和茶也提供一些烟酸。在植物(特别是成熟的谷类如玉米和小麦)中,烟酸可以以糖苷的形式与糖分子结合。因此,烟酸可存在于植物提取物中。
葫芦巴碱可存在于多种植物中,所述植物例如为生咖啡豆和经烘焙的咖啡豆,Trigonellafoenumgraecum(葫芦巴,豆科),Schumanniophytonmagnifcum,(茜草科)Mappiafoetida,和Strophantusspp.等等。因此,葫芦巴碱可存在于植物提取物中。优选地,如果使用植物提取物作为烟酸和/或葫芦巴碱的来源,则植物提取物含有至少约20wt%的烟酸和/或葫芦巴碱。
或者,可如US5002641中所述由3-甲基吡啶合成生产烟酸,同时可由尼克酸合成制造葫芦巴碱。合成的一个例子是DE344030(1921)″Betainesofthepyridineseries″(Merck,E.)。
发现:与运动组合使用时,烟酸和/或葫芦巴碱能够提高肌肉重量,并且在不使用肌肉或不费力地使用肌肉时能够延迟肌肉萎缩的发生。
优选地,烟酸和/或葫芦巴碱或其盐或酯作为营养完全膳食的部分被施用,即与充足或最优的蛋白质和/或维生素供应配合使用。优选地,维生素应包括维生素D和/或维生素D代谢产物,例如25-羟基维生素D3。烟酸和/或葫芦巴碱和/或其盐或酯与蛋白质和/或维生素的组合也是本发明的一部分。
因为烟酸和/或葫芦巴碱在兽医学以及人医学中具有应用,所以本发明的另一方面是烟酸和/或葫芦巴碱在非人动物中改善肌肉健康的用途,所述非人动物特别是赛马、狗、骆驼或用于赛跑或用作驮兽(packanimal)的其他动物,或由于其强壮而被使用的其他动物。烟酸和/或葫芦巴碱可以被施用给健康动物,或被施用给受伤/生病的动物以加速它们的康复。
上文定义的烟酸和/或葫芦巴碱具有这些特定的益处,而不向膳食中引入卡路里:
●帮助预防肌肉损失
●与运动一起支持健康的肌肉功能
●帮助预防老年性肌肉萎缩(风险降低、降低严重性、延迟发展)
●帮助在疾病期间或手术后预防肌肉损失,从而有助于更快康复和更短的住院期
●帮助在老年人中预防脆弱,从而有助于改善的活动性(mobility),生活品质并帮助延缓独立生活能力的丧失
●当环境阻止个体运动时帮助个体保持肌肉发育
●支持有效率的运动程序
●支持抗阻运动程序(例如健身或重量训练)的效力
●支持从肌肉损伤中恢复
●帮助个体更久地保持运动成功/训练效果
●帮助个体更久地保持体型/状况
●帮助个体寻找需要的身体力量
●帮助保持肌肉强度
●与运动一起改善身体组成
●支持身体调整(bodytoning)和塑身
●促进成肌细胞分化
●促进肌肉分化
●促进肌肉生长
●促进肌肉形成
●促进肌肉恢复和修复
●与运动组合时促进肌肉肥大
我们惊讶地发现,当骨骼肌适应刺激如训练时,烟酸和/或葫芦巴碱帮助肌肉负荷(肥大(hypertrophy))或去负荷(萎缩(atrophy))。另外,烟酸和/或葫芦巴碱帮助强化训练的效果并预防骨骼肌损失。因此,与运动/肌肉负荷组合时,烟酸和/或葫芦巴碱支持有效率的训练程序并促进肌肉肥大。可以观察到这些效果。
因此,烟酸和/或葫芦巴碱帮助预防老年性肌肉萎缩,老年人中的脆弱(frailty),和由于疾病、手术和较长住院期而卧床休息期间的肌肉损失。另外,烟酸和/或葫芦巴碱促进肌肉恢复和修复。
剂量:
尽管剂量可以变化,但是烟酸或葫芦巴碱剂量范围对人类而言可从每天至少5mg起;优选地对人类而言每天5到5,000mg;更优选地对人类而言每天10到3000mg,进一步更优选地每人每天50-500mg。动物剂量是类似的,并且可以针对动物的重量相应地调整。
使用烟酸和葫芦巴碱的混合物的情况下,剂量是指烟酸和葫芦巴碱的累积重量,并且剂量范围对人类而言可从每天至少5mg起;优选地对人类而言每天5到5,000mg,更优选地对人类而言每天10到3000mg,进一步更优选地对人类而言每天50-500mg。动物剂量是类似的,并且可以针对动物的重量相应地调整。
根据本发明,烟酸和/或葫芦巴碱存在于膳食、营养药物或药物组合物中。优选的组合物包含烟酸和/或葫芦巴碱和合适的膳食、营养药物或药物载体。本发明的膳食制品或营养药物可以是消费者可接受的任何形式,包括功能性食物和饮料。
合适的营养形式的例子包括多种食物和饮料,包括小杯饮料(shots)、谷物棒或其他棒状食品、饮品、富含蛋白质的饮品、补剂、方便饮料、泡腾剂等等。尤其优选的是适用于运动营养的形式,包括饮料、蛋白质粉末、棒、补剂和方便饮料。
展示以下的非限制性例子来更好地阐述本发明。
实施例1肌细胞模型
我们首先使用通常被用于研究肌肉适应的C2C12小鼠成肌细胞,体外测试了葫芦巴碱对成肌细胞分化的影响。
在生长培养基(Dulbecco改良的Eagle培养基(DMEM),补充有10%FBS、2mML-谷氨酰胺、1mM丙酮酸盐/酯、50IU/ml青霉素、50ug/ml链霉亲和素)中将C2C12细胞接种在96孔胶原蛋白-I平板(1600细胞/孔)上,直至达到100%汇合,约耗时3天。然后使用含有DMSO(对照)或10μg/ml葫芦巴碱单水合物的分化培养基(DMEM、2%FBS、2mML-谷氨酰胺、1mM丙酮酸盐/酯、50IU/ml青霉素、50ug/ml链霉亲和素)诱导细胞分化24小时。将所有孔中的最终DMSO浓度标准化至0.5%。将细胞在37℃下于5%CO2中培养。
在室温下用3.7%甲醛溶液(稀释于生长培养基中的37%甲醛,使用前过滤除菌)将细胞固定10分钟,并用1xDPBS(1xDulbecco磷酸盐缓冲的盐水)洗涤两次。之后用0.1%TritonX-100(稀释于1xDPBS)中透化2分钟。将样品用1xDPBS加2%BSA封闭1小时。对肌细胞标记而言,用1∶20的抗-α-肌球蛋白重链抗体(MF-20)将细胞标记1小时。用1xDPBS洗涤样品,并用二抗(1xDPBS中1∶250Alexa488IgG抗小鼠二抗加1∶2000Hoechst)荧光标记1小时。最后,将细胞用1xDPBS洗涤两次并密封平板,在ArrayScanHCS读数器上成像。
对于图像分析而言,使用BioApplicationMorphologyExplorer.V2,在ArrayScanHCS读数器上定量用肌球蛋白标记的肌管。选择具有大于500的对象面积(ObjectArea)和大于1000的对象总强度(ObjectTotalIntensity)的肌细胞。来自一式三份的样品的肌细胞数量展示于图1中。观察到葫芦巴碱将C2C12小鼠成肌细胞中的分化提高36%。
实施例2体内效果
为了证实我们的体外结果,首先在肥大动物模型中测试葫芦巴碱,以观察肌肉负荷期间的效果。去除来自动物一条后肢的腓肠肌,从而通过多种机制在跖肌和比目鱼肌中诱导代偿性肥大。所述模型增加肌肉负荷/训练下的肌肉重量。其刺激有体力活动的普通人或运动员的人体状况,以支持运动期间的骨骼肌功能。
运送体重18-20g的雌性C57B1/6小鼠,并给其一周的时间适应设施。在研究开始时,将动物随机分为两组(每组10只动物)。
麻醉动物并固定动物的左后肢。通过腓肠肌上的皮肤制造一个小的切口。暴露整个腓肠肌及其肌腱。从下层完整的肌肉上小心分割腓肠肌的两头,小心不要弄断神经和血管。用丝线闭合皮肤,使动物单独返回它们的笼子中。从麻醉中恢复后,动物能够立刻毫无问题地活动。所有动物接受镇痛药。以300mg/kgBW每日剂量的葫芦巴碱盐酸化物,通过强饲法处理动物三周,对照组接受载剂。
使用该技术我们鉴定并定量了经手术的腿(pQCT-测量)中跖肌和比目鱼肌和未经手术的腿(重量测量)中腓肠肌、跖肌和比目鱼肌的增加的骨骼肌重量。经手术的腿中的肥大是去除腓肠肌后剩余肌肉的代偿反应。未经手术的腿中的肥大归因于特殊的训练效果,因为所述腿使用得更多。
在接受葫芦巴碱的组中,未经手术的腓肠肌(相对于体重)的湿重增加7%(图2)。
来自未经手术腿的所有被分析的肌肉的绝对和(与动物体重相比的)相对湿重均增加。
在经手术的腿中,使用计算机断层扫描术(computer-tomography)测量评估的总腿体重和肌肉横截面积也增加。数据展示于表1中。
表1
这些结果显示,在负荷(腓肠肌手术后,肌肉肥大)/训练条件下,动物中的骨骼肌湿重增加。
实施例3肌肉萎缩
为了延伸我们的体外和体内结果,我们还对测试骨骼肌去负荷(萎缩条件)期间葫芦巴碱的效果感兴趣。因此,我们进行的第二个体内研究是使动物的后肢去负荷,从而诱导骨骼肌萎缩。
尾悬挂导致动物去负荷的后肢中的骨骼肌萎缩。结果可以被转换成人的情况:老年性肌肉萎缩(衰老过程期间骨骼肌质量和强度的退化损失)或骨骼肌的固定化(例如长期卧床休息后)。
运送体重18-20g的雌性C57B1/6小鼠,并给其一周的时间适应设施。在研究开始时,将动物随机分为两组(每组10只动物)。
之后将各组置于特殊的笼中,并使后肢去负荷(尾悬挂)三周的时间。所有小鼠单独居住,并且能够不加限制地取用饲料和水。以300mg/kg/BW每日剂量的葫芦巴碱盐酸化物,通过强饲法处理动物三周,对照组接受载剂。
我们发现腓肠肌(相对于体重)的湿重增加9%(图3),这是统计学显著的结果。
我们还比较了来自经手术的后肢的其他两种肌肉(跖肌和比目鱼肌)。下表2中所示结果显示与对照动物相比,用葫芦巴碱盐酸化物处理的动物中肌肉湿重的增加(绝对肌肉重量)。另外,将肌肉重量针对体重标准化时,用葫芦巴碱盐酸化物处理的动物证实有增加的肌肉重量/体重比(相对肌肉重量),即改善的身体组成。用葫芦巴碱盐酸化物处理时,一条腿中肌肉的总重(全腿相对于体重)也显著增加。总腿面积和肌肉腿面积的计算机断层扫描术证实,葫芦巴碱盐酸化物处理增加了骨骼肌质量。
表2
*显著性:p≤0.05
结果显示在动物去负荷/萎缩时,动物总腿横截面积、肌肉重量增加;即与对照相比,在补充葫芦巴碱的动物中不活动期间更多肌肉质量得到保持。
实施例4
耐久能力
为了测试葫芦巴碱在未经训练的动物中的效果,我们在三周的处理时间段后进行了最大耐久能力(endurance)测试。
运送体重18-20g的雌性C57B1/6小鼠,并给其一周的时间适应设施。在研究开始时,将动物随机分为两组(每组10只动物)。所有小鼠单独居住,并且能够不加限制地取用饲料和水。以300mg/kg/BW每日剂量的葫芦巴碱盐酸化物,通过强饲法处理动物三周,对照组接受载剂。
为了顺应(acclimatization),两周后将动物在踏车上放置5分钟。在解剖动物之前两天进行最大耐久能力测试。
我们发现,两组中腓肠肌的湿重是相等的(图4),如同评价的其他肌肉的湿重一样(数据未展示)。另外,3周的葫芦巴碱补充未影响未经训练的动物的耐久能力。
这些结果显示,葫芦巴碱对未经训练的小鼠中的耐久能力和骨骼肌质量没有影响。
Claims (5)
1.葫芦巴碱和/或其盐作为活性成分用于制造下述营养药物制品或食物制品的用途,所述营养药物制品或食物制品在较少肌肉活动的时期期间降低肌肉损失量,其中葫芦巴碱和/或其盐的量的范围对人类而言为每天至少5mg。
2.根据权利要求1所述的用途,其用于人使用。
3.根据权利要求1所述的用途,其用于非人动物使用。
4.根据权利要求1-3中任一项所述的用途,其还与蛋白质和/或维生素组合。
5.根据权利要求4所述的用途,其中所述维生素是维生素D或其代谢产物。
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JP2022538584A (ja) * | 2019-07-05 | 2022-09-05 | ソシエテ・デ・プロデュイ・ネスレ・エス・アー | 骨格筋における状態又は障害を予防又は治療するための、トリゴネリン及びミネラルを使用する組成物及び方法 |
CN114072147A (zh) * | 2019-07-05 | 2022-02-18 | 雀巢产品有限公司 | 使用葫芦巴碱和高蛋白质来预防或治疗骨骼肌病症或障碍的组合物和方法 |
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